The incretin hormone, glucagon-like peptide (GLP-1) is secreted from gastrointestinal endocrine cells in response to food intake. GLP-1 enhances insulin secretion from pancreatic beta cells via activation of GLP-1 receptor, a G-protein linked receptor, and increases of intracellular cAMP levels. GLP-1 is a promising new approach for treatment of non-insulin dependent diabetes mellitus (NIDDM) since GLP-1 has been shown to have antidiabetogenic action. However, there is little information about the structural components in either GLP-1 or its receptor which mediate GLP-1 action. We are interested to study the structure-function relationship of GLP-1 and its receptor as a means of understanding and potentially enhancing the action of GLP-1 as a therapeutic agent. In our study we have used GLP-1 and exendin-4 to determine the binding and receptor activation sites of the peptides. Exendin-4 is a peptide isolated from Gila monster venom which has 50 % homology to GLP-1. Using peptides which combine GLP-1 and exendin-4 sequences and using truncated peptides, we have identified analogs of GLP-1 with a wide range of binding and cell physiologic properties. Our data suggest specific regions of the GLP-1 molecule are implicated for binding and receptor activation properties. This suggests the exciting possibility of designing more potent analogs of GLP-1 and/or longer lasting analogs of GLP-1 that would be useful in NIDDM therapy. Our goal is to devote efforts to identify important residues and structures in GLP-1 peptide and GLP-1 receptor with the goal of finding improved therapy for NIDDM.